## Subject non compliance (or product failure?) [Study As­sess­ment]

Hi Loky do,

» if a subject didn't have any evaluable concentrations for only test product all intervals are BLQ and according to our SOPs and SAP, the BLQ is considered "zeros", could be excluded from PK …

Even if the outcome of investigations is negative, likely it would ring the alarm bells of regulators, esp. since you found no concentrations after the test product. What if it was a product failure (example: bad coating of a gastro-resistant PPI)? Regulators are more relaxed about the reference product since it “works” in clinical practice despite occasional failures. The EMA accepts exclusion in exceptional cases:
• MR-GL Section 6.2.3
[…] non-existing or aberrant concentration profiles. If the incidence of this outlier behaviour is observed with a comparable frequency (e.g. the number of cases is not numerically higher in the test product) in both, test and reference product, data of a period with non-existing or aberrant profile can be excluded from statistical analysis provided that it has been pre-specified in the study protocol. In a 2-period trial this will result in the subject being removed from the analysis.
• Dasatinib
In order to avoid the bias introduced by the randomly occurring low-lier values under fasting
con­ditions, it is considered acceptable that low-lier profiles can be excluded from statistical analysis […] if they occur with the same or lower frequency in the test product compared to the reference product.
(my emphases)

In your case (test only) cards are stacked against you.

» … and statistical analysis?

$$\lim_{x \to 0} \log x=-\infty.$$For simplicity we can say that $$\small{\log 0}$$ is undefined. Hence, the common analysis based on log transformed PK metrics without excluding the subject is not possible at all.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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